Abstract

Background. We assessed the relationship between sepsis occurrence and the serum levels of angiopoietin (Ang-1, Ang-2), vascular endothelial growth factor (VEGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) in pediatric patients with cancer-related febrile neutropenia.

Methods. Fifty-two children with malignant tumors who experienced 86 episodes of febrile neutropenia (FN) were examined between June 2016 and June 2018. Each FN episode was considered a separate event and the total number of FNs were recorded (86 FN episodes = FN group). The control group consisted of 21 healthy children. Ang-1, Ang-2, VEGF-A and sFlt-1 were measured at the baseline and 48th hour of each FN episode –alongside routine characterization of inflammation (C-reactive protein; white blood cell and absolute neutrophil count).

Results. Among the episodes, 29 (34.5%) developed sepsis while 57 were classified as non-complicated FN. The baseline values of patients and controls were significantly different for Ang-1, Ang-2, VEGF and sFlt-1 values (all, p < 0.05). In the subgroup with sepsis, Ang-2 values were higher than in the subgroup without sepsis (p = 0.017). In predicting sepsis, Ang-2 had 60.7% sensitivity and 66.7% specificity at the 74.6 cut-off value (AUC: 0.662 [95%CI: 0.541 – 0.783], p = 0.022), Ang-2 / Ang-1 ratio had 65.5% sensitivity and 60.0% specificity at the 0.405 cut-off value (AUC: 0.633 [95%CI: 0.513 – 0.753], p = 0.046).

Conclusions. Our results reveal that Ang-2 and Ang-2/Ang-1 were higher in the sepsis group and Ang-2 might be a biomarker to indicate the risk of sepsis in patients with FN and/or cancer.

Keywords: sepsis, children, febrile neutropenia, angiopoietin, vascular endothelial growth factor, soluble fms-like tyrosine kinase

Copyright and license

Copyright © 2024 The Author(s). This is an open access article distributed under the Creative Commons Attribution License (CC BY), which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is properly cited.

How to cite

1.
Çakmakcı S, Sarı N, Sönmez Ç, Ergürhan İlhan İ. The role of proangiogenic cytokines in predicting sepsis in febrile neutropenic children with cancer. Turk J Pediatr 2024; 66: 90-98. https://doi.org/10.24953/turkjped.2022.635

References

  1. Stone WL, Klopfenstein KJ, Hajianpour MJ, Popescu MI, Cook CM, Krishnan K. Childhood cancers and systems medicine. Front Biosci (Landmark Ed) 2017; 22: 1148-1161. https://doi.org/10.2741/4538
  2. Celkan T, Koç BŞ. Approach to the patient with neutropenia in childhood. Turk Pediatri Ars 2015; 50: 136-144. https://doi.org/10.5152/TurkPediatriArs.2015.2295
  3. White L, Ybarra M. Neutropenic fever. Hematol Oncol Clin North Am 2017; 31: 981-993. https://doi.org/10.1016/j.hoc.2017.08.004
  4. Mantzarlis K, Tsolaki V, Zakynthinos E. Role of oxidative stress and mitochondrial dysfunction in sepsis and potential therapies. Oxid Med Cell Longev 2017; 2017: 5985209. https://doi.org/10.1155/2017/5985209
  5. Whitney JE, Silverman M, Norton JS, Bachur RG, Melendez E. Vascular endothelial growth factor and soluble vascular endothelial growth factor receptor as novel biomarkers for poor outcomes in children with severe sepsis and septic shock. Pediatr Emerg Care 2020; 36: e715-e719. https://doi.org/10.1097/PEC.0000000000001638
  6. Siner JM. A tale of two ligands: angiopoietins, the endothelium, and outcomes. Crit Care 2013; 17: 1007. https://doi.org/10.1186/cc13066
  7. van der Flier M, van Leeuwen HJ, van Kessel KP, Kimpen JL, Hoepelman AI, Geelen SP. Plasma vascular endothelial growth factor in severe sepsis. Shock 2005; 23: 35-38. https://doi.org/10.1097/01.shk.0000150728.91155.41
  8. Siner JM, Bhandari V, Engle KM, Elias JA, Siegel MD. Elevated serum angiopoietin 2 levels are associated with increased mortality in sepsis. Shock 2009; 31: 348-353. https://doi.org/10.1097/SHK.0b013e318188bd06
  9. Ricciuto DR, dos Santos CC, Hawkes M, et al. Angiopoietin-1 and angiopoietin-2 as clinically informative prognostic biomarkers of morbidity and mortality in severe sepsis. Crit Care Med 2011; 39: 702-710. https://doi.org/10.1097/CCM.0b013e318206d285
  10. Alves BE, Montalvao SAL, Aranha FJP, et al. Time-course of sFlt-1 and VEGF-A release in neutropenic patients with sepsis and septic shock: a prospective study. J Transl Med 2011; 9: 23. https://doi.org/10.1186/1479-5876-9-23
  11. Paulus P, Jennewein C, Zacharowski K. Biomarkers of endothelial dysfunction: can they help us deciphering systemic inflammation and sepsis? Biomarkers 2011; 16 Suppl 1: S11-S21. https://doi.org/10.3109/1354750X.2011.587893
  12. Luz Fiusa MM, Costa-Lima C, de Souza GR, et al. A high angiopoietin-2/angiopoietin-1 ratio is associated with a high risk of septic shock in patients with febrile neutropenia. Crit Care 2013; 17: R169. https://doi.org/10.1186/cc12848
  13. Fang Y, Li C, Shao R, Yu H, Zhang Q. The role of biomarkers of endothelial activation in predicting morbidity and mortality in patients with severe sepsis and septic shock in intensive care: a prospective observational study. Thromb Res 2018; 171: 149-154. https://doi.org/10.1016/j.thromres.2018.09.059
  14. Lehrnbecher T, Robinson P, Fisher B, et al. Guideline for the management of fever and neutropenia in children with cancer and hematopoietic stem-cell transplantation recipients: 2017 update. J Clin Oncol 2017; 35: 2082-2094. https://doi.org/10.1200/JCO.2016.71.7017
  15. Goldstein B, Giroir B, Randolph A; International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005; 6: 2-8. https://doi.org/10.1097/01.PCC.0000149131.72248.E6
  16. Ellis M. Febrile neutropenia. Ann N Y Acad Sci 2008; 1138: 329-350. https://doi.org/10.1196/annals.1414.035
  17. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345: 1368-1377. https://doi.org/10.1056/NEJMoa010307
  18. Pierrakos C, Vincent JL. Sepsis biomarkers: a review. Crit Care 2010; 14: R15. https://doi.org/10.1186/cc8872
  19. Yano K, Liaw PC, Mullington JM, et al. Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality. J Exp Med 2006; 203: 1447-1458. https://doi.org/10.1084/jem.20060375
  20. Taha Y, Raab Y, Larsson A, et al. Vascular endothelial growth factor (VEGF)-a possible mediator of inflammation and mucosal permeability in patients with collagenous colitis. Dig Dis Sci 2004; 49: 109-115. https://doi.org/10.1023/b:ddas.0000011611.92440.f2
  21. Karlsson S, Pettilä V, Tenhunen J, et al. Vascular endothelial growth factor in severe sepsis and septic shock. Anesth Analg 2008; 106: 1820-1826. https://doi.org/10.1213/ane.0b013e31816a643f
  22. Pickkers P, Sprong T, Eijk LV, Hoeven HVD, Smits P, Deuren MV. Vascular endothelial growth factor is increased during the first 48 hours of human septic shock and correlates with vascular permeability. Shock 2005; 24: 508-512. https://doi.org/10.1097/01.shk.0000190827.36406.6e
  23. Hämäläinen S, Juutilainen A, Matinlauri I, et al. Serum vascular endothelial growth factor in adult haematological patients with neutropenic fever: a comparison with C-reactive protein. Eur J Haematol 2009; 83: 251-257. https://doi.org/10.1111/j.1600-0609.2009.01260.x
  24. Kalra M, Dinand V, Choudhary S, Sachdeva A, Yadav SP. Serum vascular endothelial growth factor-a levels during induction therapy in children with acute lymphoblastic leukemia. Indian Pediatr 2013; 50: 659-662. https://doi.org/10.1007/s13312-013-0198-6
  25. Shapiro NI, Yano K, Okada H, et al. A prospective, observational study of soluble FLT-1 and vascular endothelial growth factor in sepsis. Shock 2008; 29: 452-457. https://doi.org/10.1097/shk.0b013e31815072c1
  26. Shapiro NI, Schuetz P, Yano K, et al. The association of endothelial cell signaling, severity of illness, and organ dysfunction in sepsis. Crit Care 2010; 14: R182. https://doi.org/10.1186/cc9290
  27. Tsao PN, Chan FT, Wei SC, et al. Soluble vascular endothelial growth factor receptor-1 protects mice in sepsis. Crit Care Med 2007; 35: 1955-1960. https://doi.org/10.1097/01.CCM.0000275273.56547.B8
  28. Mankhambo LA, Banda DL; IPD Study Group, et al. The role of angiogenic factors in predicting clinical outcome in severe bacterial infection in Malawian children. Crit Care 2010; 14: R91. https://doi.org/10.1186/cc9025
  29. Tsigkos S, Koutsilieris M, Papapetropoulos A. Angiopoietins in angiogenesis and beyond. Expert Opin Investig Drugs 2003; 12: 933-941. https://doi.org/10.1517/13543784.12.6.933
  30. Fiedler U, Reiss Y, Scharpfenecker M, et al. Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med 2006; 12: 235-239. https://doi.org/10.1038/nm1351
  31. Bhandari V, Choo-Wing R, Lee CG, et al. Hyperoxia causes angiopoietin 2-mediated acute lung injury and necrotic cell death. Nat Med 2006; 12: 1286-1293. https://doi.org/10.1038/nm1494
  32. Giuliano JS, Lahni PM, Harmon K, et al. Admission angiopoietin levels in children with septic shock. Shock 2007; 28: 650-654. https://doi.org/10.1097/shk.0b013e318123867b
  33. Alves BE, Montalvao SAL, Aranha FJP, et al. Imbalances in serum angiopoietin concentrations are early predictors of septic shock development in patients with post chemotherapy febrile neutropenia. BMC Infect Dis 2010; 10: 143. https://doi.org/10.1186/1471-2334-10-143
  34. Mimaroğlu E, Çıtak EÇ, Kuyucu N, Eskendari G. The diagnostic and prognostic value of angiopoietins compared with C-reactive protein and procalcitonin in children with febrile neutropenia. Turk J Pediatr 2017; 59: 418-425. https://doi.org/10.24953/turkjped.2017.04.008